ABSTRACT Nucleic acid aptamers have shown great promise as the synthetic alternative to monoclonal antibodies (mAbs) in therapeutics, diagnostics, and R&D tools. Despite their key advantages of chemical and thermal stability, consistent quality, sequenceability and amplifiability, aptamers are used far less widely than mAbs, primarily due to poor performance in real-life applications. The root of the aptamer performance problem lies in the limited chemical diversity offered by the 4 natural nucleic acid bases, in contrast to the 20 different amino acids composing antibody. Fortunately, as a synthetic scaffold, aptamers have the potential to incorporate a broad range of chemical diversity through use of modified nucleotides. However, due to fundamental limitations of selection-based discovery methods (SELEX), chemically modified aptamers are just beginning to scratch the surface, and have been largely limited to a single type of modification - deoxyuracil carrying hydrophobic functional groups. The potential of a broad range of modified bases for aptamer discovery and application is yet uncharted. We propose to develop Chemically-Augmented Particle Display (CAPD), a novel approach that enables us to discover modified aptamers with a broad range of chemical diversity that exhibit greatly improved affinity, specificity, stability in biological media and the capability serve as a viable alternative to antibodies in real-world applications. Our method has the potential to screen a wide range of distinct chemically modified aptamer libraries, wherein we measure the affinity and specificity of every aptamer candidate and explicitly isolate the highest performance binders with the best chemical modifications. In phase I, we will develop the CAPD platform and validate aptamers generated with it in standard ELISA assays in serum and compare to natural DNA aptamers and commercial mAbs. In phase II, we will then develop a production pipeline to create and validate an initial catalog of aptamer pairs to address unmet needs in the research and diagnostics markets. We will deliver aptamer pairs for no less than 30 priority targets (identified by our customers and healthcare stakeholders) for use in point of care diagnostics and research assays as which are severely underserved by antibodies. We will make all these aptamers immediately available for research and diagnostics markets. If successful, we believe CAPD will revolutionize aptamer discovery, and enable synthetic aptamers to achieve mainstream adoption in biomedical research, diagnostics and therapeutics.